1. Field of the Invention
The invention relates to an improved process for the preparation of Azithromycin monohydrate. More particularly, the invention is directed to a more simplified process for the preparation of Azithromycin monohydrate that circumvents the need to use cumbersome and/or inefficient extraction and/or isolation procedures.
2. Description of the Related Art
Azithromycin (Formula (1)) (USAN generic name for 9-Deoxo-9a-aza-9a-methyl-9a-homo-erythromycin A) is a 15 membered ring macrolide belonging to a new class of antibiotics termed “Azalides”, due to the incorporation of a nitrogen atom in the macrocyclic ring: 
11-(4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-2-ethyl-3,4,10-trihydroxy-13-(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy)-3,5,6,8,10,12,1 4-heptamethyl-1-oxa-6-aza-cyclopentadecan-15-one (Formula (1)) Azithromycin is derived from the 14-membered macrolide antibiotic erythromycin A and shows significant improvement in its activity against gram—Ve organisms compared to erythromycin A (C. J. Dunn and L. B. Barradell Azithromycin: A Review of its Pharmacological properties and use as a 3-day therapy in respiratory tract infections, Drug, 1996, March, 51(3)483-505). The numbering scheme for Azithromycin is indicated in Formula (1) below (which is equivalent to the same Formula (1) depicted above): 
Azithromycin was first discovered by G. Kobrehel and S. Djokic (Belgium Patent No. 892357; related U.S. Pat. No. 4,517,359; S. Djokic et al. J. CHEM. RESEARCH (S), 1988, 132 and idem miniprint, 1988, 1239). U.S. Pat. No. 4,517,359 describes reductive methylation of 11-aza-10-deoxo-10-dihydro erythromycin A (presently called 9-Deoxo-9a-aza-9a-homoerythromycin A) performed with an excess of formaldehyde and formic acid in a halogenated hydrocarbon, e.g., chloroform or carbon tetrachloride. In the procedure described in U.S. Pat. No. 4,517,359,the isolation of Azithromycin involves extraction of the aqueous layer with a halogenated hydrocarbon solvent followed by evaporation of the solvent. The disadvantages of this process are that (i) a halogenated hydrocarbon is used which is environmentally unsafe and (ii) the isolation of azithromycin involves several cumbersome and/or inefficient extraction and solvent evaporation steps.
It is, therefore, an object of this invention is to provide an improved process for preparation of Azithromycin monohydrate, in which the reductive methylation of 9-Deoxo-9a-aza-9a-homoerythromycin A is carried out in a non-halogenated solvent (for example, acetonitrile) and Azithromycin monohydrate crystals are precipitated directly from the reaction mixture without the involvement of cumbersome extraction and/or concentration steps as are described above in relation to U.S. Pat. No. 4,517,359.
Other objects of the invention will be apparent to those of ordinary skill in the art based on the disclosure of this application.